Biology subjects

Rapp, A. W.

Publications and source records attributed to Rapp, A. W..

2 recordsLinked to original sources

bioRxiv2026

Trans-Kingdom dsRNA Sensing: Aspergillus fumigatus Mycovirus Activates MDA5/MAVS Immunity and Limits Allergic Bronchopulmonary Aspergillosis

MDA5 is a cytosolic pattern-recognition receptor (PRR) that binds to double-stranded RNA (dsRNA) and subsequently interacts with the signaling adaptor protein MAVS to initiate the antiviral interferon (IFN) response. Our group previously demonstrated that MDA5 is essential for host resistance against the fungal pathogen, Aspergillus fumigatus. Although fungal dsRNA was sufficient to activate MDA5 signaling, the precise source of A. fumigatus dsRNA responsible for this MDA5-stimulating function remains unknown. Here, we demonstrate that the magnitude of the IFN-dependent antifungal response is A. fumigatus strain dependent. Unexpectedly, we found that A. fumigatus isolates infected with dsRNA mycoviruses triggered a more robust MAVS-dependent inflammatory response within alveolar macrophages. Furthermore, dsRNA mycovirus infection increased fungal susceptibility to antifungal killing without altering other A. fumigatus growth characteristics. Although dsRNA mycovirus infection did not alter virulence in an acute bronchopneumonia model of A. fumigatus infection, it significantly impaired virulence and improved disease parameters in a chronic model of allergic bronchopulmonary aspergillosis (ABPA). Collectively, these findings reveal a novel role for trans-kingdom interactions in driving the host antifungal IFN response and modulating virulence in chronic aspergillosis models.

immunology↗

bioRxiv2024

TGFβ primes alveolar-like macrophages to induce type I IFN following TLR2 activation

Alveolar macrophages (AMs) are key mediators of lung function and are potential targets for therapies during respiratory infections. TGF{beta} is an important regulator of AM differentiation and maintenance, but how TGF{beta} directly modulates the innate immune responses of AMs remains unclear. This shortcoming prevents effective targeting of AMs to improve lung function in health and disease. Here we leveraged an optimized ex vivo AM model system, fetal-liver derived alveolar-like macrophages (FLAMs), to dissect the role of TGF{beta} in AMs. Using transcriptional analysis, we first globally defined how TGF{beta} regulates gene expression of resting FLAMs. We found that TGF{beta} maintains the baseline metabolic state of AMs by driving lipid metabolism through oxidative phosphorylation and restricting inflammation. To better understand inflammatory regulation in FLAMs, we next directly tested how TGF{beta} alters the response to TLR2 agonists. While both TGF{beta} (+) and TGF{beta} (-) FLAMs robustly responded to TLR2 agonists, we found an unexpected activation of type I interferon (IFN) responses in FLAMs and primary AMs in a TGF{beta}-dependent manner. Surprisingly, mitochondrial antiviral signaling protein and the interferon regulator factors 3 and 7 were required for IFN production by TLR2 agonists and the IFN response was dependent on mitochondrial reactive oxygen species. Together, these data suggest that TGF{beta} modulates AM metabolic networks and innate immune signaling cascades to control inflammatory pathways in AMs.

immunology↗